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Epigenetic dysregulation leads to aberrant DNA hypermethylation and is common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). A large number of clinical trials in AML, MDS, and other hematologic malignancies have assessed hypomethylating agents (HMAs), used alone or in combination with other drugs, in the frontline, maintenance, relapsed/refractory, and peritransplant settings. Effective maintenance therapy has long been a goal for patients with AML in remission. Previous large, randomized clinical trials of maintenance with HMAs or other agents had not shown meaningful improvement in overall survival. Oral azacitidine (Oral-AZA [CC-486]) is approved in the United States, Canada, and European Union for treatment of adult patients with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy who are ineligible for hematopoietic cell transplant. Regulatory approvals of Oral-AZA were based on outcomes from the randomized, phase III QUAZAR AML-001 trial, which showed a median overall survival advantage of 9.9 months with Oral-AZA versus placebo. Oral-AZA allows convenient extended AZA dosing for 14 days per 28-day treatment cycle, which is not feasible with injectable AZA. Focusing on AML and MDS, this report reviews the rationale for the use of orally bioavailable AZA and its potential use in all-oral combination therapy regimens; the unique pharmacokinetic and pharmacodynamic profile of Oral-AZA compared with injectable AZA; the clinical safety and efficacy of Oral-AZA maintenance therapy in patients with AML in first remission and for treatment of patients with active MDS; and ongoing Oral-AZA clinical trials.

TP53 gene mutations are common in myelodysplastic syndromes (MDS). Previous studies have reported their detrimental effects on patient survival. However, current treatment strategies mainly based on hypomethylating agent therapy (HMA) and hematopoietic stem cell transplantation (HSCT) still leave a lot to be desired. And there is also a lack of studies on large sample with a view to the refinement of specific characteristics and disease progression. So we performed a meta-analysis including 20 studies compromising 5067 patients to assess the prognostic impact and clinical characteristics of TP53 mutations in MDS patients. The overall hazard ratio for overall survival (OS) was 2.14 (95% confidence interval 1.94-2.37, P.00001) compared with patients with MDS without TP53 mutations. Lower progression-free survival and leukemia-free survival were associated with TP53 mutations. Subgroup analysis revealed that TP53 mutations were significantly associated with high levels of blast cells and karyotypic aberrations. And among Asian population, the adverse impact on OS of TP53 mutations seemed worse than those in Western countries. (HR 2.87 vs. 2.02, P = .01). In addition, TP53 mutations had no effect on response to HMA therapy, and HSCT improved OS in patients carrying TP53 mutations.

The treatment landscape for acute myeloid leukemia has expanded significantly in the past 5 years with the approval of several therapeutic small molecules. While agents such as FLT3 inhibitors and IDH inhibitors are restricted for patients with specific mutations, the selective BCL-2 inhibitor venetoclax combined with a hypomethylating agent or low-dose cytarabine was approved after demonstrating frontline efficacy across a molecularly heterogenous group of patients. Currently, venetoclax is being investigated in combination with multiple other therapies as the role of the intrinsic apoptotic pathway in acute myeloid leukemia continues to be explored.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that is classified as Merkel cell polyomavirus (MCPyV)-positive or virus-negative. Epigenetic changes, such as DNA methylation, can alter gene expression and influence cancer progression. However, patterns of DNA methylation and the therapeutic efficacy of hypomethylating agents have not been fully explored in MCC. We characterized genome-wide DNA methylation in 16 MCC cell lines from both molecular subclasses in comparison to other cancer types, and found that the overall profile of MCC is similar to small cell lung carcinoma. Comparison of virus-positive and -negative MCC revealed 2,260 differentially methylated positions. The hypomethylating agent decitabine (DAC) upregulated expression of antigen-presenting machinery in MCC cell lines and stimulated membrane expression of HLA-A in virus-positive and virus-negative MCC xenograft tumors. DAC also induced prominent caspase- and large T antigen-independent cell death in virus-positive MCC, whereas virus-negative MCC cell lines displayed decreased proliferation without increased cell death. In mouse xenografts, decitabine significantly decreased the size of virus-positive tumors, but not virus-negative tumors. Our findings indicate that viral status predicts genomic methylation patterns in MCC, and that DAC may be therapeutically effective against MCC via anti-proliferative effects, cell death, and increased immune recognition.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin‐based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5‐aza deoxy‐cytosine (5‐aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5‐aza‐resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin‐resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5‐aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5‐aza and 5‐aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5‐aza‐resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin‐resistant cells, which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5‐aza‐resistant cells, the exact opposite changes seen in cisplatin‐resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2, and BMI1, conferred 5‐aza resistance and cisplatin sensitization, and mediated genome‐wide repression of polycomb target gene expression. Finally, genome‐wide analysis revealed that 5‐aza‐resistant, cisplatin‐resistant, and DNMT3B‐knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5‐aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs., Alternative therapies are needed for testicular germ cell tumors (TGCTs) refractory to cisplatin. Recent preclinical and clinical studies suggest that cisplatin refractory TGCTs are distinctly sensitive to hypomethylating agents. The current study suggests a reciprocal relationship between cisplatin and hypomethylation agent sensitivity in TGCTs involving DNMT3B and the polycomb pathway that could lead to biomarkers for future clinical trials.

Oncofetal protein SALL4 is critical for cancer cell survival. Targeting SALL4, however, is only applicable in a fraction of cancer patients who are positive for this gene. To overcome this limitation, we propose to induce a cancer vulnerability by engineering a partial dependency upon SALL4. Following exogenous expression of SALL4, SALL4-negative cancer cells became partially dependent on SALL4. Treatment of SALL4-negative cells with the FDA-approved hypomethylating agent 5-aza-2′-deoxycytidine (DAC) resulted in transient upregulation of SALL4. DAC pretreatment sensitized SALL4-negative cancer cells to entinostat, which negatively affected SALL4 expression through a microRNA, miRNA-205, both in culture and in vivo. Moreover, SALL4 was essential for the efficiency of sequential treatment of DAC and entinostat. Overall, this proof-of-concept study provides a framework whereby the targeting pathways such as SALL4-centered therapy can be expanded, sensitizing cancer cells to treatment by transient target induction and engineering a dependency. Significance: These findings provide a therapeutic approach for patients harboring no suitable target by induction of a SALL4-mediated vulnerability.

Background: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. Methods: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax+HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. Results: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60days of therapy. Infections were confirmed as the most common nonhematologic adverse event. Conclusions: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax+HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax+HMA effectiveness and toxicities in real life.

Dear Editor, Acute myeloid leukemia is the most common sub-type of acute leukemia in adulthood [1]. It has a detrimental prognosis with conventional combination chemotherapy, mainly with anthracyclines and cytarabine. Allogeneic stem cell transplantation has signifcantly prolonged the overall survival in a particular “eligible” patient population, but as AML is a disorder of the elderly, not all patients are able to proceed with allogeneic stem cell transplantation.

Key Points Effector polyfunctional index score of CD4 cells was more associated with responses to combined azacitidine/nivolumab than CD8 cells.Single-cell biomarker assays can be used in predicting responses to immune-based therapies., Acute myeloid leukemia (AML) remains a difficult disease to treat disease. In a phase 2 clinical trial in patients with relapsed/refractory AML, combining the hypomethylating agent, azacitidine, with the PD-1 checkpoint inhibitor, nivolumab, demonstrated encouraging response rates (33%), median event-free, and overall survival, compared with a historical cohort of contemporary patients treated with azacitidine-based therapies, with an acceptable safety profile. Biomarkers of response are yet to be determined. In this study, we leveraged a multiplexed immune assay to assess the functional states of CD4+ and CD8+ cells at a single-cell level in pretherapy bone marrows in 16 patients with relapsed/refractory AML treated with azacitidine/nivolumab. Effector CD4+ but not CD8+ cells had distinct polyfunctional groups and were associated with responses and better outcomes. Further evaluation of the polyfunctional strength index composition across cell types revealed that interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were the major drivers of enhanced polyfunctionality index of pretherapy CD4+ subset, whereas Granzyme B, IFN-γ, MIP-1b, and TNF-α drove the nonsignificantly enhanced pretreatment Polyfunctional Strength Index of CD8+ subset in the responders. Single-cell polyfunctional assays were predictive of response in AML and may have a potential role as a biomarker in the wider sphere of immunotherapy.

Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

PURPOSE OF REVIEW The antitumor activity of macrophages is regulated by a balance of prophagocytic and antiphagocytic signals. Cluster of differentiation 47 (CD47), the dominant macrophage immune checkpoint ('do not eat me' signal), interacts with its receptor signal-regulatory protein alpha (SIRPα) to suppress phagocytic activities. This axis plays a pivotal role in immune evasion in myeloid malignancies as well as multiple cancers providing strong rationale for therapeutic exploitation. RECENT FINDINGS Preclinical studies have revealed overexpression of CD47 on leukemic stem cells and myeloblasts from patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), which contributes to immune surveillance evasion and is associated with poor outcomes. Blockade of CD47 with different approaches has demonstrated proof-of-concept antitumor activities mainly through phagocytic clearance. Early phase clinical trials combining the anti-CD47 mAb magrolimab with the hypomethylating agent azacitidine have showed synergistic activities, deep and durable responses, as well as a tolerable safety profile in these patients, including those with TP53 mutations. SUMMARY Targeting CD47/SIRPα axis, in combination with other therapeutic agents, represents a promising treatment approach for patients with myeloid malignancies, particularly the challenging TP53-mutated subgroup.

Хронічні мієлопроліферативні неоплазми (МПН), що трансформуються в гострий мієлоїдний лейкоз (ГМЛ)/мієлодиспластичний синдром (МДС), МПН у фазі акселерації або первинний мієлофіброз (ПМФ) високого ризику характеризуються рефрактерністью до терапії і дуже короткою тривалістю життя хворих. У патогенезі пухлинного процесу важливу роль відіграють епігенетичні зміни головних генів-супресорів пухлинного росту. Опубліковані дані щодо дослідження активності інгібітору ДНК метилтрансферази (5-азацитидину). У 54 пацієнтів із МПН (включаючи 21 пацієнта з есенціальною тромбоцитемією (ЕТ), 21 пацієнта з істинною поліцитемією (ІП), 7 пацієнтів із первинним мієлофіброзом і 5 пацієнтів із некласифікованими) розвинувся бластний криз або мієлодиспластичний синдром (n = 28). Пацієнти отримували 5-азацитидин у дозі 75 мг/м2 підшкірно щодня протягом 7 днів кожні 4 тижні. Загальна відповідь зареєстрована у 52 % пацієнтів (у 24 % — повна ремісія, у 11 % — часткова ремісія, у 8 % — кістковомозкова або ремісія з цитопенією, у 9 % — гематологічне поліпшення). Тривалість медіан відповіді становила 9 місяців. Повернення в хронічну фазу захворювання спостерігалося у 39 % пацієнтів, які відповіли на лікування. Медіана загальної виживаності становила 11 місяців. Мієлосупресія була головним небажаним ефектом, із 3–4-м ступенем нейтропенії у 10 (29 %) пацієнтів. Представлений перший власний позитивний досвід використання 5-азацитидину (Виндуза, компанія «Др. Реддіс Лабораторіз») у пацієнта С. із бластним кризом. Часткова ремісія розвинулася у пацієнта після 3 курсів 5-азацитидину і триває протягом 4 місяців спостереження.

TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design.

Despite improvements in first‐line treatment of T‐cell acute lymphoblastic leukemia (T‐ALL), the outcome of relapsed T-ALL remains dismal with less than 7% achieving a long-term survival. Thus, there is an unmet need for new treatment strategies to improve outcomes in this setting. Suppression of apoptosis is one of the hallmarks of anticancer drug resistance. Hence, over the past few years, antiapoptotic proteins have become an attractive target for therapeutic intervention in several hematologic malignancies. Venetoclax (ABT-199) is a novel, orally bioavailable small-molecule inhibitor of B-cell lymphoma 2 (BCL-2), a key regulator of the intrinsic apoptotic pathway. Recent preclinical studies have suggested that inhibition of BCL-2 may be a novel therapeutic strategy for patients with T-ALL. Herein, we report a case of clinical response to venetoclax in combination with a hypomethylating agent in a patient with relapsed T-ALL after allogeneic stem cell transplant and review the existing literature.

The authors declared the following potential conflict of interest with respect to the research, authorship, and/or publication of this article: T.B. has received support for attending meetings and/or travel from Jazz Pharmaceutical, honoraria from Jazz Pharmaceutical, BMS, and Pfizer. D.V. has received honoraria from Celgene/BMS, Amgen, Novartis, Jazz Pharmaceuticals, and Pfizer and support for attending meetings and/or travel from Amgen, BMS/Celgene, and Jazz. M.D.-C. reports honoraria and membership on entity's Board of directors or advisory committees from Novartis, BMS, and Takeda. Dr G.S. has received personal fees from AbbVie, Amgen, and Astellas and has received research funding from Celgene/BMS Janssen-Cilag, Novartis, Roche, and Takeda. Background: The consequences of infectious toxicity of hypomethylating agents (HMAs) on overall survival (OS) of patients diagnosed with high-risk myeloid neoplasms have not been thoroughly investigated. Objectives: We aimed to evaluate whether infectious events (IEs) negatively influenced the results of HMA treatment in a real-world setting. Design: Observational study. Methods: We obtained data from 412 non-selected consecutive patients from 23 Spanish hospitals who were diagnosed with high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia and were treated with HMA. HMAs received after chemotherapy or stem cell transplant were excluded. All IEs were recorded. Outcomes included OS, modifications to the pre-planned treatment, incidence and characteristics of IEs, hospitalization, red blood cell transfusions, and factors associated with infection. Results: The rate of infection was 1.2 per patient/year. Next-cycle delay (p = 0.001) and hospitalizations (p = 0.001) were significantly influenced by IEs. Transfusion requirements during each cycle were significantly higher after infection compared with cycles without infection (coefficient = 1.55 [95% confidence interval (CI) = 1.26-1.84], p < 0.001). The median number of cycles was lower in patients experiencing any infection during the first four cycles (5 [3-8] versu 8 [5-16], p < 0.001). In the multivariable analysis, factors associated with lower OS were having any infection during the first four cycles (hazard ratio (HR) = 1.43 [95% CI = 1.09-1.88], p = 0.01), bone marrow blasts ⩾30% (HR = 2.13 [95% CI = 1.14-3.96], p = 0.01), adverse cytogenetics (HR = 1.70 [95% CI = 1.30-2.24], p < 0.001), and platelet count 20% (HR = 1.57 [95% CI = 1.19-2.01], p < 0.001) and adverse cytogenetics (HR = 1.7 [95% CI = 1.35-2.14], p < 0.001) were associated with infection, whereas hemoglobin >9 g/dl (HR = 0.65 [95% CI = 0.51-0.82], p < 0.001) and higher platelet count (HR = 0.997 [95% CI = 0.996-0.998], p = 0.016) protected from it. Conclusion: HMA infectious toxicity worsens OS, hinders the adherence to antineoplastic treatment and results in significant morbidity. Preventive strategies are fundamental in vulnerable patients.

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.

BACKGROUND Academic studies have proved that anti-programmed death-1 (PD-1) monoclonal antibodies demonstrated remarkable activity in relapsed/refractory classical Hodgkin lymphoma (cHL). However, most patients ultimately experienced failure or resistance. It is urgent and necessary to develop a novel strategy for relapsed/refractory cHL. The aim of this case report is to evaluate the combination approach of low-dose decitabine plus a PD-1 inhibitor in relapsed/ refractory cHL patients with prior PD-1 inhibitor exposure. CASE SUMMARY The patient was a 27-year-old man who complained of enlarged right-sided cervical lymph nodes and progressive pain aggravation of the right shoulder over the past 3 mo before admission. Histological analysis of lymph node biopsy was suggestive of cHL. The patient experienced failure of eight lines of therapy, including multiple cycles of chemotherapy, PD-1 blockade, and anti-CD47 antibody therapy. Contrast-enhanced CT showed that the tumors of the chest and abdomen significantly shrunk or disappeared after three cycles of treatment with decitabine plus tislelizumab. The patient had been followed for 11.5 mo until March 2, 2021, and no progressive enlargement of the tumor was observed. CONCLUSION The strategy of combining low-dose decitabine with tislelizumab could reverse the resistance to PD-1 inhibitors in patients with heavily pretreated relapsed/ refractory cHL. The therapeutic effect of this strategy needs to be further assessed.

Azacitidine (AZA), a hypomethylating agent, is the standard treatment for patients with myelodysplastic syndromes (MDS). However, responses are generally transient in approximately 50% of patients. Cytomorphology and immunophenotyping are widely used in the treatment of MDS. Therefore, the present study investigated the relationship between immunophenotyping and the outcomes of MDS patients administered AZA as first-line therapy. We retrospectively examined the relationship between immunophenotyping and the outcomes of 118 MDS patients administered AZA as first-line therapy. The response to AZA was poorer in patients with a CD33/CD34 ratio > 1 than in those with a CD33/CD34 ratio 1 as independent adverse prognostic factors for overall survival. A Kaplan–Meier analysis showed that a CD33/CD34 ratio > 1 was associated with poor survival. In the present study, a CD33/CD34 ratio > 1 in blast cells was associated with poor survival in MDS patients administered AZA as first-line therapy.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high‐risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is the only curative option for patients suffering from high‐risk AML/MDS. However, many patients relapse after allo‐HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL‐2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft‐versus‐host disease (GVHD) and boost the graft‐versus‐leukemia (GVL) effect post‐transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low‐dose decitabine (LDEC) plus VEN to prevent relapse after allo‐HSCT for high‐risk AML/MDS patients. Twenty patients with high‐risk AML (n = 17) or high‐risk MDS (n = 3) post‐transplantation were recruited. Approximately day 100 post‐transplantation, all patients received LDEC (15 mg/m2 for 3 d) followed by VEN (200 mg) on d 1‐21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event‐free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo‐HSCT. Survival outcomes were assessed using Kaplan‐Meier analysis. The median follow‐up was 598 (149‐1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2‐y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2‐y EFS time was 525 (149‐1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo‐HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high‐risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high‐risk AML/MDS patients., The results of the current study suggest that maintenance treatment with LDEC combined with VEN introduced nearly 3 mo after allo‐HSCT is efficacious, with an acceptable toxicity profile and impressive long‐term disease control.

The definition of older age in AML is arbitrary. In the context of the clinical studies, it starts with age ≥60 or ≥65 years and in recent years ≥70 or 75, depending on the selection of the studied population. In clinical practice, with older age, we often mean that the patient is unfit for intensive chemotherapy. Higher age overlaps with categories such as worse performance status, unfitness, comorbidities, poor-risk cytogenetics, adverse mutation patterns, age-related clonal haematopoiesis and specific disease ontogeny. Intensive induction therapy can result in prolonged overall survival, at least in a subset of elderly patients aged up to 75 years despite the reluctance of some physicians and patients to use treatment regimens perceived as toxic. Venetoclax and azacitidine combination is the new standard of comparison for persons unfit for intensive therapy. New oral hypomethylating agent CC-486 as maintenance therapy led to a prolonged overall survival in a randomized trial of patients ≥55 years of age who were in first complete remission, but not eligible for allogeneic stem cell transplantation. Any therapy is better than no therapy, but a substantial proportion of older patients still receive only palliative care. Making a decision for AML diagnosed in older age should be individualized and shared through the dialog with the patient and relatives or cohabitants, considering medical issues and social factors including personal goals. Although we are witnesses of the advances in basic research and therapy, we are still a very long way from curing older patients with AML.

Patients with Myelodysplastic syndromes (MDS) have few therapy options for sustainable responses in the frontline setting, and even less after hypomethylating agent (HMA) failure in relapsed and refractory setting. The only potential cure is an allogeneic hematopoietic stem cell transplant which is an unrealistic option for the majority of MDS patients. Immunotherapy with checkpoint inhibition, CAR-T cells, and vaccine therapy few have shown promise in a variety cancer and have now been tested in patients with MDS. Most trials have focused on AML patients and included small numbers of MDS patients. Until now, a dedicated review of immunotherapy outcomes in MDS patients has been lacking. Thus, herein we review outcomes of MDS patients after immunotherapies on a variety of clinical trials reported to date.

Venetoclax (Ven) combined with a hypomethylating agent (HMA) has now emerged as an effective treatment regimen for acute myeloid leukemia, in both de novo and relapsed/refractory setting. The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast‐phase myeloproliferative neoplasm (MPN‐BP). Pre‐leukemic phenotype included essential thrombocythemia (ET)/post‐ET myelofibrosis (34%), polycythemia vera (PV)/post‐PV myelofibrosis (38%) and primary myelofibrosis (28%). Twenty‐nine study patients were fully annotated cytogenetically and molecularly (NGS): 69% harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%) and U2AF1 (7%). All patients received Ven combined with either azacitidine (n = 12) or decitabine (n = 20); either up front (n = 23) or after failing another induction therapy (n = 9). Complete remission with (CR) or without (CRi) count recovery was achieved in 14 (44%) patients and was more likely to occur in the absence of pre‐leukemic PV/post‐PV myelofibrosis phenotype (p

Accelerated and blast phase myeloproliferative neoplasms are advanced stages of the disease with historically a poor prognosis and little improvement in outcomes thus far. The lack of responses to standard treatments likely results from the more aggressive biology reflected by the higher incidence of complex karyotype and high-risk somatic mutations, which are enriched at the time of transformation. Treatment options include induction chemotherapy (7 + 3) as that used on de novo acute myeloid leukemia or hypomethylating agent-based therapy, which has shown similar outcomes. Allogeneic stem cell transplantation remains the only potential for cure.